The role of IL-33 and ST2 in innate and adaptive inflammation

Inflammation is the body's response to injury and infection, and is aimed at eradicating the threat and repairing the tissue through the activation of the innate and adaptive immune systems. The innate inflammatory response is triggered by a surveillance network of broadly specific receptors. It is immediate and preprogrammed, and involves the activation of phagocytic cells and the release of soluble anti-microbial mediators to eradicate infection as quickly as possible. It can also promote the subsequent adaptive response. The adaptive inflammatory response is regulated by antigen-specific T helper (Th) lymphocytes, and has memory to provide immunity against repeat infection. These two arms of the immune system are often activated concurrently and communicate through the release of cytokines and chemokines to co-ordinate and regulate an appropriate response. Th cells differentiate into various effector cell types and co-ordinate different responses, often directing innate immune cells to carry out effector functions. Th1 cells produce IFNgamma and direct responses against intracellular pathogens through macrophage activation. Th2 cells produce IL-4, IL-5 and IL 13 and are important in resistance to parasites through mast cell and eosinophil activation. Th17 cells produce IL-17 and are important in sepsis through neutrophil activation. Dysregulation of these responses often contributes to the development of disease. Autoimmune diseases are characterised by Th1 and/or Th17 inflammation, whilst dysregulated Th2 responses result in allergy and asthma. Inflammatory diseases are often chronic and debilitating, and current therapies are either ineffective or have significant side effects, so novel inflammatory mechanisms and therapeutic targets are required. ST2L is a member of the IL-1 receptor family that was identified as a surface marker for Th2 cells, and is associated with Th2 cell activation and functions, although its precise role is unknown. IL 33 is a novel member of the IL-1 cytokine family, and has recently been identified as a ligand for ST2L. It promotes Th2 cytokine release and eosinophil accumulation in vivo. sST2 is a soluble form of ST2L that has broad immunosuppressive activity, although the mechanism is unknown. Therefore IL-33 and ST2 are potentially important inflammatory mediators, and in this thesis I aimed to demonstrate the role of IL-33 and ST2 in innate and adaptive inflammation, using murine models of allergic airways disease and autoimmune arthritis. I have shown that IL-33 administered directly to the airways provokes an innate Th2 type response in the lung with many characteristics in common with allergic airways disease. There was increased production of Th2 cytokines, except IL-4, chemokines and eosinophilic inflammation. ST2 gene knockout (ST2-/-) mice demonstrated this response was dependent on ST2, and SCID mice demonstrated that whilst non-lymphoid cells were sufficient to initiate a response, lymphoid cells enhanced it. IL-33 exacerbated the effector phase of Th2 allergic airways inflammation, with increased eosinophils, Th2 cytokines and chemokines in the airway, and increased lymph node responses. (ST2-/-) mice had reduced inflammation in the airway, despite normal lymph node responses, suggesting the role of IL-33 and ST2 is more important in the tissues. Pilot data also suggested that IL-33 exacerbates Th1/Th17 autoimmune collagen-induced arthritis (CIA), with increased disease severity and lymph node responses. ST2-/- mice had reduced disease severity, again despite normal lymph node responses. In summary, 1 have demonstrated that in the airway IL-33 is sufficient to induce a Th2 type innate response with pathological features similar to asthma. I have also shown that IL-33 can exacerbate Th2 mediated airway inflammation, and in addition, Th1/Th17 mediated arthritis. Thus it has general pro-inflammatory actions, and warrants further investigation to elucidate the mechanisms involved and fulfil its potential as a target for future therapeutic intervention

Pharmacologically Distinct Nicotinic Acetylcholine Receptors Drive Efferent-Mediated Excitation in Calyx-Bearing Vestibular Afferents

Electrical stimulation of vestibular efferent neurons rapidly excites the resting discharge of calyx/dimorphic (CD) afferents. In turtle, this excitation arises when acetylcholine (ACh), released from efferent terminals, directly depolarizes calyceal endings by activating nicotinic ACh receptors (nAChRs). Although molecular biological data from the peripheral vestibular system implicate most of the known nAChR subunits, specific information about those contributing to efferent-mediated excitation of CD afferents is lacking. We sought to identify the nAChR subunits that underlie the rapid excitation of CD afferents and whether they differ from α9α10 nAChRs on type II hair cells that drive efferent-mediated inhibition in adjacent bouton afferents. We recorded from CD and bouton afferents innervating the turtle posterior crista during electrical stimulation of vestibular efferents while applying several subtype-selective nAChR agonists and antagonists. The α9α10 nAChR antagonists, α-bungarotoxin and α-conotoxin RgIA, blocked efferent-mediated inhibition in bouton afferents while leaving efferent-mediated excitation in CD units largely intact. Conversely, 5-iodo-A-85380, sazetidine-A, varenicline, α-conotoxin MII, and bPiDDB (N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide) blocked efferent-mediated excitation in CD afferents without affecting efferent-mediated inhibition in bouton afferents. This pharmacological profile suggested that calyceal nAChRs contain α6 and β2, but not α9, nAChR subunits. Selective blockade of efferent-mediated excitation in CD afferents distinguished dimorphic from calyx afferents by revealing type II hair cell input. Dimorphic afferents differed in having higher mean discharge rates and a mean efferent-mediated excitation that was smaller in amplitude yet longer in duration. Molecular biological data demonstrated the expression of α9 in turtle hair cells and α4 and β2 in associated vestibular ganglia

Multinucleon emission following the pion absorption in N, Ar and Xe

Positive pion absorption was studied in an almost 4p geometry allowing simultaneous measurements of various charge and neutral multiplicities. Total absorption cross sections and its decomposition into the most important channels is determined. The results are presented for N, Ar and Xe nuclei at incident pion energies of 118,162 and 239 MeV. The role of multinucleon emission in the absorption process is emphasized

Pion absorption in ^4He

This paper presents a large solid angle measurement of the positive pion absorption cross section on ^4He and its decomposition into partial channels. A large fraction of the absorption cross section at incident pion kinetic energies of T_π+ =70, 118, 162, 239, and 330 MeV is due to multinucleon channels

Multinucleon emission following the pion absorption in N, Ar and Xe

Positive pion absorption was studied in an almost 4p geometry allowing simultaneous measurements of various charge and neutral multiplicities. Total absorption cross sections and its decomposition into the most important channels is determined. The results are presented for N, Ar and Xe nuclei at incident pion energies of 118,162 and 239 MeV. The role of multinucleon emission in the absorption process is emphasized

COVID-19 associated with extensive pulmonary arterial, intracardiac and peripheral arterial thrombosis

We describe a patient with COVID-19 who developed simultaneous pulmonary, intracardiac and peripheral arterial thrombosis. A 58-year-old man, without major comorbidity, was admitted with a 14-day history of breathlessness. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection was confirmed by laboratory testing. Initial imaging revealed COVID-19 pneumonia but no pulmonary thromboembolism (PTE) on CT pulmonary angiography (CTPA). The patient subsequently developed respiratory failure and left foot ischaemia associated with a rising D-dimer. Repeat CTPA and lower limb CT angiography revealed simultaneous bilateral PTE, biventricular cardiac thrombi and bilateral lower limb arterial occlusions. This case highlights a broad range of vascular sequalae associated with COVID-19 and the fact that these can occur despite a combination of prophylactic and treatment dose anticoagulation

IL-33 Exacerbates Eosinophil-Mediated Airway Inflammation

IL-33 has emerged as an important mediator in the immunopathogenesis of allergy and asthma. However, the role of IL-33 in eosinophil-mediated inflammation has not been fully explored. In this article, we report that IL-33 directly stimulates eosinophil differentiation from CD117(+) progenitors in an IL-5-dependent manner. Although resting eosinophils expressed moderate levels of the IL-33R alpha-chain (ST2L), eosinophils that accumulated in the airways of mice with OVA-induced asthma expressed increased amounts of ST2L. In vitro, IL-33 and GM-CSF are potent inducers of ST2L expression on eosinophils, and IL-33 induced the production of IL-13, CCL17, and TGF-beta by eosinophils. In adoptive-transfer experiments, IL-33 exacerbated eosinophil-mediated airway inflammation by increasing the levels of eosinophils, macrophages, lymphocytes, IL-13, TGF-beta, CCL3, CCL17, and CCL24 in the lungs. IL-33 also enhanced the eosinophil-mediated differentiation of airway macrophages toward the alternatively activated macrophage phenotype in an IL-13-dependent manner. Taken together, this study demonstrates that the IL-33/ST2 signaling pathway activates airway eosinophils that exacerbate airway inflammation in an autocrine and paracrine manner

A role of IL-33 in bone turnover

No abstract available

A role of IL-33 in bone turnover

No abstract available